The activation of resting B-cells from G.sub.0 to G.sub.1 phase of the cell cycle and the subsequent induction of activated B-cells to proliferate are distinct steps requiring distinct regulatory mechanisms. Some agents, including murine B-cell stimulating factor-pl (BSF-pl) (Rabin, et al., 1985, Proc. Nat. Acad. Sci. USA 82, 2935-2939) or low doses of anti-immunoglobulin (anti-Ig) (DeFranco, et al., 1985, J. Immunol. 135:87-94; Wetzel, et al., 1984, J. Immunol. 133:2327-2332; DeFranco, et al., 1982, J. Exp. Med. 155:1523-1536; Muraguchi, et al., 1984, J. Immunol. 132:176-180), are "activation" or "competence" factors. That is, they induce B-cells to enlarge, synthesize more RNA, and enter G.sub.1, but alone they do not induce DNA synthesis in B-cells. Other "growth" factors, such as human B-cell growth factor (BCGF) and interleukin-2 (IL-2) cause activated B-cells to traverse the cell cycle and enter S phase but do not trigger resting B-cells (Kehrl, et al., 1984, Immunol. Rev. 18:75-96; Muraguchi, et al., 1984, J. Immunol. 132:176-180; Zubler, et al. 1984, J. Exp. Med. 60:1170-1183; Jung, et al., 1984, J. Exp. Med. 160:1597-1604).
A number of factors that promote the growth Of B-cells have now been described by investigators of both murine and human systems. These include B-cell growth factors (BCGF) derived from several different sources including T-cell lines or hybridomas, B-cell lines, or dendritic cells. Although both interleukin-1 (IL-1) and interleukin-2 (IL-2) have been shown to augment B-cell growth, they apparently are distinct from certain BCGFs. For instance, monoclonal antibodies (mAb) to a murine BCGF (O'Hara, et al., 1985, Nature (Lond.) 315:333) or human BCGF (Ambrus, et al., 1985, J Exp. Med. 162:1319) block BCGF activity but not IL-1 or IL-2 activity. Although distinct from IL-1 or IL-2, the BCGFs themselves appear to be heterogeneous based on biochemical data and differential activity on different B-cell subsets or costimulation assays. For instance, 60-kilodalton (kDa) high-molecular-weight human BCGF, BCGF (high), has been identified that is distinct from a 12-kDa low-molecular-weight form, BCGF (low) (Ambrus, et al., 1985, J. Clin. Invest. 75:732). The cDNA encoding a 20-kDa murine BCGF, tentatively designated B-cell stimulating factor pl (BSF-pl), has recently been cloned and sequenced (Noma et al., 1986, Nature 319:640). The recombinant lymphokine not only has BCGF activity but can also activate resting B-cells and induce the differentiation of IgG.sub.1 producing cells; thus it differs from human BCGF (high) and BCGF (low) both in its molecular weight and in its range of activity.
These activation and growth signals presumably regulate cells by interacting with specific B-cell surface structures. In addition to the antigen-specific signal through surface Ig, several other candidate B-cell surface polypeptides have been identified that may in some way function in the activation or growth of B-cells. For instance, the cell surface receptors for IL-1 (Dower, et al., 1985, J. Exp. Med. 160:501) and IL-2 (Robb et al., 1984, J. Exp. Med. 160:1126) have been characterized, and recently functional IL-2 receptors have been identified on B-cells (Zubler, et al., 1984, J. Exp. Med. 160:1170; Jung, et al., 1984, J. Exp. Med. 160:1597; Muraguchi, et al., 1985, J. Exp. Med. 161:181). However, receptors for B-cell growth and activation factors have yet to be fully characterized. Several candidate B-cell surface polypeptides have been identified that may in some way function in the activation or growth of B-cells. For example, Subbarao and Mosier (Subbarao, et al., 1983, Immunol. Rev. 69:81-97) found that monoclonal antibodies (mAb) to the murine B-cell antigen Lyb2 activate B-cells, and recently evidence has been presented suggesting Lyb2 may be the receptor for BSF-pl (Yakura, 1985, Fed. Proc. 44:1532). Similarly, we have found that appropriate mAb (1F5) to a 35 kDa polypeptide, Bp35, activates human B-cells from G.sub.0 into G.sub.1 (Clark, et al., 1985, Proc. Nat. Acad. Sci. USA 82:1766-1770; Gollay, et al., 1985, J. Immunol. 135:3795-3801). Aggregated C3d or antibodies to the 140 kDa C3d receptor, Bp140, cause proliferation of B-cells that are T-cell dependent (Melchers, et al., 1985, Nature 317:264-267; Nemerow, et al., 1985, J. Immunol. 135:3068-3073; Frade et al., 1985, Eur. J. Immunol. 15:73-76). Although BCGFs have been identified in both mouse and man, the receptors for these factors have not yet been isolated. Wang and coworkers (Wang, et al., 1979, J. Exp. Med. 149:1424-1433) made a polyclonal antisera that identified a 54-kDa polypeptide (gp54) on human B-cells and showed that the rabbit antisera to gp54 induced tonsillar B-cells to divide. Recently, Jung and Fu (Jung, et al., 1984, J. Exp. Med. 160:1919-1924) isolated a mAb (AB-1) to a 55-kDa antigen restricted to activated B-cells that blocks BCGF-dependent proliferation. However, whether or not either anti-gp54 or AB-1 recognize a BCGF receptor is not yet known.